ArticleGenes & development2015
Structural basis for substrate recognition by the human N-terminal methyltransferase 1.
Article in Genes & development, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- Prognostic significance of NTMT1 and its association with tumor progression in oral squamous cell carcinoma.Frontiers in oncology · 2026Article
- Proteoform-predictor: Increasing the Phylogenetic Reach of Top-Down Proteomics.Journal of proteome research · 2025Article
- A snapshot of the Physcomitrella N-terminome reveals N-terminal methylation of organellar proteins.Plant cell reports · 2024Article
- Structural basis of tRNA recognition by the mNature structural & molecular biology · 2024Article
- Intrafamily heterooligomerization as an emerging mechanism of methyltransferase regulation.Epigenetics & chromatin · 2024Review
- Multicomponent Oxidative Nitrile Thiazolidination Reaction for Selective Modification of N-terminal Dimethylation Posttranslational Modification.Journal of the American Chemical Society · 2023Article
- Impact of Protein NLife (Basel, Switzerland) · 2023Review
- Structure-Activity Relationship Studies of Venglustat on NTMT1 Inhibition.Journal of medicinal chemistry · 2023Article
- Article
- Optimizing purification and activity assays of N-terminal methyltransferase complexes.Methods in enzymology · 2023Article
- Design and characterization of PROTAC degraders specific to protein N-terminal methyltransferase 1.European journal of medicinal chemistry · 2022Article
- Methyltransferases: Functions and Applications.Chembiochem : a European journal of chemical biology · 2022Review
- Single-cell architecture and functional requirement of alternative splicing during hematopoietic stem cell formation.Science advances · 2022Article
- Structure, Activity and Function of the Dual Protein Lysine and Protein N-Terminal Methyltransferase METTL13.Life (Basel, Switzerland) · 2021Review
- Discovering the N-Terminal Methylome by Repurposing of Proteomic Datasets.Journal of proteome research · 2021Article
- Past, present, and perspectives of protein N-terminal methylation.Current opinion in chemical biology · 2021Review
- Chemoproteomic Study Uncovers HemK2/KMT9 As a New Target for NTMT1 Bisubstrate Inhibitors.ACS chemical biology · 2021Article
- Structure-based Discovery of Cell-Potent Peptidomimetic Inhibitors for Protein N-Terminal Methyltransferase 1.ACS medicinal chemistry letters · 2021Article
- Post-translational Modifications of the Protein Termini.Frontiers in cell and developmental biology · 2021Review
- Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies.Journal of medicinal chemistry · 2020Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
α-N-terminal methylation represents a highly conserved and prevalent post-translational modification, yet its biological function has remained largely speculative. The recent discovery of α-N-terminal methyltransferase 1 (NTMT1) and its physiological substrates propels the elucidation of a general role of α-N-terminal methylation in mediating DNA-binding ability of the modified proteins. The phenotypes, observed from both NTMT1 knockdown in breast cancer cell lines and knockout mouse models, suggest the potential involvement of α-N-terminal methylation in DNA damage response and cancer development. In this study, we report the first crystal structures of human NTMT1 in complex with cofactor S-adenosyl-L-homocysteine (SAH) and six substrate peptides, respectively, and reveal that NTMT1 contains two characteristic structural elements (a β hairpin and an N-terminal extension) that contribute to its substrate specificity. Our complex structures, coupled with mutagenesis, binding, and enzymatic studies, also present the key elements involved in locking the consensus substrate motif XPK (X indicates any residue type other than D/E) into the catalytic pocket for α-N-terminal methylation and explain why NTMT1 prefers an XPK sequence motif. We propose a catalytic mechanism for α-N-terminal methylation. Overall, this study gives us the first glimpse of the molecular mechanism of α-N-terminal methylation and potentially contributes to the advent of therapeutic agents for human diseases associated with deregulated α-N-terminal methylation.
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